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Sudden death from bronchial asthma following injection of pyromen
SUDDEN
DEATH
C.
H. A.
FROM BRONCHIAL ASTHMA INJECTION OF PYROMEN
WAI,TON,
M.D.,
AND
WINNIPEG,
Q.
B.
ELLIOTT,
FOLLOWING
M.B.
Ca~mn
T
HERE have been many reports of death from astl1ma.l This case is reported because of its somewhat unusual circumstances. The patient was a white married woman, thirty-one years old at the time of her death (Sept. 14, 1951). She had been under nearly continuous observation since April 16, 1948. During her first pregnancy in September, 1945, she suffered symptoms suggestive of asthma but no record existed of such a diagnosis. At that time she was said also to have toxemia with hypertension. She remained well after that until early in her second pregnancy when in July, 1947, she developed allergic rhinitis with early polyp formation. In Sept., 1947, she had mild asthma and this recurred at intervals until her second baby was born in February, 1948. In March, 1948, she underwent a nasal polypectomy and a bilateral radical antrostomy. Following this, her asthma became very severe and intractable. There was no known family history of allergy. The patient was depressed and anxious and there was a considerable amount of domestic discord. Her physical examination showed the usual pulmonary findings of severe asthma. The nasal mucosa was reddened and there was evidence of continued polyposis. A mucopurulent nasal discharge was noted. There was moderate arterial hypertension and her ocular fundi showed arteriolar changes, classified as grade I. She was underweight. Blood examination revealed a hemoglobin content of 11.8 Gm., 4,010,OOO red blood cells, 8,350 leukocytes, and of these 16 per cent were eosinophils. Urinalysis yielded normal findings. She was tested to the common inhalants, intradermally, but failed to react except very slightly to some fungus spores, feathers, kapok, and tobacco. The history indicated marked aspirin sensitivity. A test elimination diet was carried out. The results of this were inconclusive but the patient was certain that she did not tolerate wheat, onion, chocolate, and egg and usually left these articles out of her diet. During the early phase of her management she was deeply disturbed psychologically. She suffered from anxiety reactions, personality conflicts, feelings of inferiority, tension, insecurity, and an inability to get along with her husband. In June, 1948, she took an overdose of bromides, accidentally, and this led to an acute psychosis necessitating her admission to the psychopathic hospital. Up to this time her asthma had been severe and nearly intractable. When she b,ecame psychotic her asthma subsided almost completely and all abnormal physical signs disappeared from her chest. She recovered from her acute psychotic episode quickly and was discharged within seventeen days. Immediately her asthma returned so severely that she required several hypodermic injections of epinephrine daily. *From the Division of Medicine, The Winnipeg Winnipeg General Hospital. Received for publication Dec. IO, 1951. 322
Clinic,
and
the
Department
of Pathology,
WALTON
AND
ELLIOTT
:
SUDDEN
DEATH
FROM
ASTHMA
323
For the next six months she presented a difficult therapeutic problem but was able to carry on at home. She had a remission in March and April, 1949 but during the following summer had gradually increasing asthma. During t,his time and the following winter she required periodic relief of intercurrent infections with antibiotics and with frequent use of symptomatic measures carried on fairly well until a very severe asthmatic state necessitated admission (her first in thirty months) to hospital in November, 1950.
Fig.
l.-Section ary
through lung bronchi, vesicular
root
showing emphysema
mucosal and
thickening enlarged
and mucous bronchopulmonary
plugging in secondnodes.
There was moderate improvement while in the hospital but she relapsed soon after discharge and readmission was necessary on February 10, 1951. Her inability to respond to any medication led to the use of ACTH. After 500 mg. given over a period of five days, she became free of all signs and symptoms. Her psychological problems went into ab.eyance and she seemed well in every way. Within two weeks need of medication returned. However, she managed to carry on with only minimal difficulty until late March, 1951, when symptoms again increased considerably and were almost intractable on her admission to hospital again on July 6, 1951. She received 280 mg. ACTH over a period of four days, most of it intravenously, and made another dramatic recovery, going home free of signs and symptoms on July 12, 1951. Symptoms began to recur on July 31, 1951, and increased steadily. These symptoms were aggravated by much vomiting and she was readmitted to hospital on August 31, 1951, because of vomiting and a fainting attack. Her asthma was not especially severe. Epinephrine, rectal aminophyllin and inhaled Isuprel was required daily but she was able to be up and about the ward and she was not as severely incapacitated as on previous occasions. present in her chest, but dyspnea was moderate Signs of asthma were constantly and she slept well. Her condition did not warrant the use of ACTS.
324
THE
JOURNAL TABLE
I)ATE
7 Sept.
51.
8 Sept.
51.
9 Sept.
51.
10 He@.
51.
II
Sept.
51.
12
Sept.
51.
13 Sept 11 Sept.
51. .51.
-____-
I I
INTRAVENOUS PYROMEN
1 microgram (0.1 C.C.) 2 micrograms (0.2 C.C.) 3 micrograms (0.3 C.C.) 3 mi~rograrns
(0.3 C.C.) 5 micrograms (0.5 cc.) 3 micrograms (0.3 C.C.) None used 5 miczrograms (0.5 C.C.)
OP
ALLERGY
T.
,:E.,~‘TIoN
I
--(lhilliness.
T.99”F.
Slight
shivering.
T.99.3”1’.
Slight
shivering.
T.SO.Y”F.
?io
waetion
Flushed-no temperature. No reaction
elevation
of
Ko immediate reaction-then rapidly increasing dyspnea X5 minutes.
and
death
in
It was decided to give her a trial on Pyromen” therapy,* and this was done as shown in Table I. No immediate reaction occurred following her last intravenous injection of Pyromen and although she still manifested ast,hnlatic
Fig. eosinophils. ruptured.
Z.-Tertiary Dark At the
wavy lower
bronchus, lumen 2 mm., occluded by mucus which line made up of nuclei of epithelium, the free is a distended mucous gland duct. right corner
contains num erous border of whi ch is
signs throughout her chest she was not specially dyspneic nor was she cyancxed. Shortly afterwards, dyspnea increased and she asked for epinephrine. I1p to this time the ward staff were not alarmed, but when epinephrine in repe ,ated *Pyromen is a nonprotein bacterial complex polysaccharide. It is prepared and distributed by Travenol, Inc. The Inc.
pyrogen, by the material
the active factor Baxter Laboratories, used in this case
in which appears to be a Inc., Morton Grove, 111. provided by Trarenol,
was
\\‘ALTOS
AND
ELIJOTT
:
SUDDEN
DEATH
PROM
ASTHMA
325
doses was without effect, administration of intravenous aminophyllin was Before this could requested because of rapid deterioration in her condition. be started she suddenly became deeply cyanosed, breath sounds became almost inaudible and she died suddenlp one hour and twen@five minutes after the Pyromen had been injected intravenously.
Fig. S-Section of \\-a11 of tertiary bronchus. e
From bottom to top: circular muscle and markedly infiltration ; basement membrane rupture. Lumen filled with mucus containcells. Magnification XZOF.
‘~IYY~1’sY I ,
An :tutop:~p (IV. (:. II. h-S:j(i::) ~vvas performed to, exclude common (‘auses of sudtlen (loath, confirm the tliaxnosis of bronchial asthma, and to observe any effrrt of Pyrorne~~ External c~xaminatinn was normal except for cyanosis of the face and nail beds, evident twenty-four hours after tleath. The cardiovascular system showed heart weight of 240 grams, right rc,ntriclc wall 2 mm. thick, no dilatation of either ventriclr, no valvular, coronary artery, myocardial, arterial or venous abnormality. There was no thrombosis or embolism; pulmonary vessels and femoral veins contained fluid blood. The kidneys showed congested parenchyma Lut were otherwise normal as were the ureters, bladder, and pelvic organs. The gastrointestinal tract, liver, pancreas, spleryn, and adrenals mere normal. As tha patient had been in hospital for a period of two weeks no examinations for poisons WWP carried out. Skull, meninges, and brain showed no lesion except for a few petechial hemorrhagra over the right posterior parietal region. Microscopic examinations of all brain sections and i hex pituitary showed marked congestion. The thyroid weighed 15 grams and contained colloid. The thymus weighed 20 grams, was bilobed with a soft pink cut surfa.ce.
326
THE
JOURNAL
OF
ALLERGY
The nares and fauces were patent, and the tongue not swollen or bitten. The larynx, trachea, and main bronchi were congested and contained a little clear sticky mucus but were not obstructed. The whole lungs were voluminous and crepitant. After fixation by formalin perfusion and immersion they were sliced at 4 mm. intervals, and showed findings characteristic of bronchial asthma, namely, most secondary and tertiary bronchi completely occluded by thick tenaceous plugs, and a fine honeycomb appearance of the parenchyma characteristic of emphysema. ?io atelectasis, consolidation, or scars were seen. The pleura was normal. Rronchopulmonary lymph nodes were enlarged to 2 by 1.5 by 1.5 cm., in contrast to the other nodes of the body which were average. Microscopic examination showed dinuse mucus plugging of medium and small bronchioles with rupture of lining epithelium, swollen basement membrane, prominent mucus glands with ducts greatly distended by mucus, marked bronchial wall edema and alveoli distended, and empty except for a few free mononuclear cells. Numerous eosinophils were noted in hilar lymph node sinuses, lung venules, bromhial \I-alls, and lumen where they were most numerous near the mucosa. Except of the lungs
for visceral congestion the only pathological which presented the picture characteristically
findings of importance were those seen in sudden death from asthma.1
SUMMARY
1. A case of sudden and unexpected death from asthma following the intravenous use of Pyromen is presented. This young woman had an intrinsic type of asthma starting in pregnancy and becoming very severe after a double radical antrum operation. She was aspirin sensitive. 2. The patient had been psychologically unstable and during one acute psychotic phase became temporarily and completely free of asthma. 3. Two courses of ACTH, in February and July, 1951, respectively, produced complete remissions of asthma for a few weeks and led to temporary psychological stability. 4. Her fourth admission to hospital was characterized by less severe asthma t.han on previous occasions. Therapy with Pyromen produced no beneficial effects of any kind and her last treatment with this substance was followed by very rapidly increasing bronchial obstruction and death within eighty-five minutes. The fatal termination was not anticipated because although she had required daily medication her asthma was not severe at the time and she was ambulant. 5. Asthmatic patients of this type have a notoriously bad prognosis and often require very little to upset their delicately balanced respiratory state. Whether or not the use of Pyromen was causally related to her death it is impossible to say. It can be said with certainty that Pyromen had no demonstrable beneficial effect. 6. The pathological findings were limited to the respiratory tract. These showed a striking example of intense bronchial and bronchiolar obstruction due to mucus plugging and mucosal edema. The thymus was persistent. Death was due to asphyxia. REFERENCES
1. Walton,
C. H. A., Penner, D. W., and Wilt, J. C.: Sudden Death From Asthma, Can. Med. Assoc. J. 64: 95, 1951. Pyromen in the Treatment of Perennial Allergic 2. Randolph, T. G., and Rollins, J. P.: Symptoms, Ann. Allergy 8: 626, 1950.
DEATH
C.
H. A.
FROM BRONCHIAL ASTHMA INJECTION OF PYROMEN
WAI,TON,
M.D.,
AND
WINNIPEG,
Q.
B.
ELLIOTT,
FOLLOWING
M.B.
Ca~mn
T
HERE have been many reports of death from astl1ma.l This case is reported because of its somewhat unusual circumstances. The patient was a white married woman, thirty-one years old at the time of her death (Sept. 14, 1951). She had been under nearly continuous observation since April 16, 1948. During her first pregnancy in September, 1945, she suffered symptoms suggestive of asthma but no record existed of such a diagnosis. At that time she was said also to have toxemia with hypertension. She remained well after that until early in her second pregnancy when in July, 1947, she developed allergic rhinitis with early polyp formation. In Sept., 1947, she had mild asthma and this recurred at intervals until her second baby was born in February, 1948. In March, 1948, she underwent a nasal polypectomy and a bilateral radical antrostomy. Following this, her asthma became very severe and intractable. There was no known family history of allergy. The patient was depressed and anxious and there was a considerable amount of domestic discord. Her physical examination showed the usual pulmonary findings of severe asthma. The nasal mucosa was reddened and there was evidence of continued polyposis. A mucopurulent nasal discharge was noted. There was moderate arterial hypertension and her ocular fundi showed arteriolar changes, classified as grade I. She was underweight. Blood examination revealed a hemoglobin content of 11.8 Gm., 4,010,OOO red blood cells, 8,350 leukocytes, and of these 16 per cent were eosinophils. Urinalysis yielded normal findings. She was tested to the common inhalants, intradermally, but failed to react except very slightly to some fungus spores, feathers, kapok, and tobacco. The history indicated marked aspirin sensitivity. A test elimination diet was carried out. The results of this were inconclusive but the patient was certain that she did not tolerate wheat, onion, chocolate, and egg and usually left these articles out of her diet. During the early phase of her management she was deeply disturbed psychologically. She suffered from anxiety reactions, personality conflicts, feelings of inferiority, tension, insecurity, and an inability to get along with her husband. In June, 1948, she took an overdose of bromides, accidentally, and this led to an acute psychosis necessitating her admission to the psychopathic hospital. Up to this time her asthma had been severe and nearly intractable. When she b,ecame psychotic her asthma subsided almost completely and all abnormal physical signs disappeared from her chest. She recovered from her acute psychotic episode quickly and was discharged within seventeen days. Immediately her asthma returned so severely that she required several hypodermic injections of epinephrine daily. *From the Division of Medicine, The Winnipeg Winnipeg General Hospital. Received for publication Dec. IO, 1951. 322
Clinic,
and
the
Department
of Pathology,
WALTON
AND
ELLIOTT
:
SUDDEN
DEATH
FROM
ASTHMA
323
For the next six months she presented a difficult therapeutic problem but was able to carry on at home. She had a remission in March and April, 1949 but during the following summer had gradually increasing asthma. During t,his time and the following winter she required periodic relief of intercurrent infections with antibiotics and with frequent use of symptomatic measures carried on fairly well until a very severe asthmatic state necessitated admission (her first in thirty months) to hospital in November, 1950.
Fig.
l.-Section ary
through lung bronchi, vesicular
root
showing emphysema
mucosal and
thickening enlarged
and mucous bronchopulmonary
plugging in secondnodes.
There was moderate improvement while in the hospital but she relapsed soon after discharge and readmission was necessary on February 10, 1951. Her inability to respond to any medication led to the use of ACTH. After 500 mg. given over a period of five days, she became free of all signs and symptoms. Her psychological problems went into ab.eyance and she seemed well in every way. Within two weeks need of medication returned. However, she managed to carry on with only minimal difficulty until late March, 1951, when symptoms again increased considerably and were almost intractable on her admission to hospital again on July 6, 1951. She received 280 mg. ACTH over a period of four days, most of it intravenously, and made another dramatic recovery, going home free of signs and symptoms on July 12, 1951. Symptoms began to recur on July 31, 1951, and increased steadily. These symptoms were aggravated by much vomiting and she was readmitted to hospital on August 31, 1951, because of vomiting and a fainting attack. Her asthma was not especially severe. Epinephrine, rectal aminophyllin and inhaled Isuprel was required daily but she was able to be up and about the ward and she was not as severely incapacitated as on previous occasions. present in her chest, but dyspnea was moderate Signs of asthma were constantly and she slept well. Her condition did not warrant the use of ACTS.
324
THE
JOURNAL TABLE
I)ATE
7 Sept.
51.
8 Sept.
51.
9 Sept.
51.
10 He@.
51.
II
Sept.
51.
12
Sept.
51.
13 Sept 11 Sept.
51. .51.
-____-
I I
INTRAVENOUS PYROMEN
1 microgram (0.1 C.C.) 2 micrograms (0.2 C.C.) 3 micrograms (0.3 C.C.) 3 mi~rograrns
(0.3 C.C.) 5 micrograms (0.5 cc.) 3 micrograms (0.3 C.C.) None used 5 miczrograms (0.5 C.C.)
OP
ALLERGY
T.
,:E.,~‘TIoN
I
--(lhilliness.
T.99”F.
Slight
shivering.
T.99.3”1’.
Slight
shivering.
T.SO.Y”F.
?io
waetion
Flushed-no temperature. No reaction
elevation
of
Ko immediate reaction-then rapidly increasing dyspnea X5 minutes.
and
death
in
It was decided to give her a trial on Pyromen” therapy,* and this was done as shown in Table I. No immediate reaction occurred following her last intravenous injection of Pyromen and although she still manifested ast,hnlatic
Fig. eosinophils. ruptured.
Z.-Tertiary Dark At the
wavy lower
bronchus, lumen 2 mm., occluded by mucus which line made up of nuclei of epithelium, the free is a distended mucous gland duct. right corner
contains num erous border of whi ch is
signs throughout her chest she was not specially dyspneic nor was she cyancxed. Shortly afterwards, dyspnea increased and she asked for epinephrine. I1p to this time the ward staff were not alarmed, but when epinephrine in repe ,ated *Pyromen is a nonprotein bacterial complex polysaccharide. It is prepared and distributed by Travenol, Inc. The Inc.
pyrogen, by the material
the active factor Baxter Laboratories, used in this case
in which appears to be a Inc., Morton Grove, 111. provided by Trarenol,
was
\\‘ALTOS
AND
ELIJOTT
:
SUDDEN
DEATH
PROM
ASTHMA
325
doses was without effect, administration of intravenous aminophyllin was Before this could requested because of rapid deterioration in her condition. be started she suddenly became deeply cyanosed, breath sounds became almost inaudible and she died suddenlp one hour and twen@five minutes after the Pyromen had been injected intravenously.
Fig. S-Section of \\-a11 of tertiary bronchus. e
From bottom to top: circular muscle and markedly infiltration ; basement membrane rupture. Lumen filled with mucus containcells. Magnification XZOF.
‘~IYY~1’sY I ,
An :tutop:~p (IV. (:. II. h-S:j(i::) ~vvas performed to, exclude common (‘auses of sudtlen (loath, confirm the tliaxnosis of bronchial asthma, and to observe any effrrt of Pyrorne~~ External c~xaminatinn was normal except for cyanosis of the face and nail beds, evident twenty-four hours after tleath. The cardiovascular system showed heart weight of 240 grams, right rc,ntriclc wall 2 mm. thick, no dilatation of either ventriclr, no valvular, coronary artery, myocardial, arterial or venous abnormality. There was no thrombosis or embolism; pulmonary vessels and femoral veins contained fluid blood. The kidneys showed congested parenchyma Lut were otherwise normal as were the ureters, bladder, and pelvic organs. The gastrointestinal tract, liver, pancreas, spleryn, and adrenals mere normal. As tha patient had been in hospital for a period of two weeks no examinations for poisons WWP carried out. Skull, meninges, and brain showed no lesion except for a few petechial hemorrhagra over the right posterior parietal region. Microscopic examinations of all brain sections and i hex pituitary showed marked congestion. The thyroid weighed 15 grams and contained colloid. The thymus weighed 20 grams, was bilobed with a soft pink cut surfa.ce.
326
THE
JOURNAL
OF
ALLERGY
The nares and fauces were patent, and the tongue not swollen or bitten. The larynx, trachea, and main bronchi were congested and contained a little clear sticky mucus but were not obstructed. The whole lungs were voluminous and crepitant. After fixation by formalin perfusion and immersion they were sliced at 4 mm. intervals, and showed findings characteristic of bronchial asthma, namely, most secondary and tertiary bronchi completely occluded by thick tenaceous plugs, and a fine honeycomb appearance of the parenchyma characteristic of emphysema. ?io atelectasis, consolidation, or scars were seen. The pleura was normal. Rronchopulmonary lymph nodes were enlarged to 2 by 1.5 by 1.5 cm., in contrast to the other nodes of the body which were average. Microscopic examination showed dinuse mucus plugging of medium and small bronchioles with rupture of lining epithelium, swollen basement membrane, prominent mucus glands with ducts greatly distended by mucus, marked bronchial wall edema and alveoli distended, and empty except for a few free mononuclear cells. Numerous eosinophils were noted in hilar lymph node sinuses, lung venules, bromhial \I-alls, and lumen where they were most numerous near the mucosa. Except of the lungs
for visceral congestion the only pathological which presented the picture characteristically
findings of importance were those seen in sudden death from asthma.1
SUMMARY
1. A case of sudden and unexpected death from asthma following the intravenous use of Pyromen is presented. This young woman had an intrinsic type of asthma starting in pregnancy and becoming very severe after a double radical antrum operation. She was aspirin sensitive. 2. The patient had been psychologically unstable and during one acute psychotic phase became temporarily and completely free of asthma. 3. Two courses of ACTH, in February and July, 1951, respectively, produced complete remissions of asthma for a few weeks and led to temporary psychological stability. 4. Her fourth admission to hospital was characterized by less severe asthma t.han on previous occasions. Therapy with Pyromen produced no beneficial effects of any kind and her last treatment with this substance was followed by very rapidly increasing bronchial obstruction and death within eighty-five minutes. The fatal termination was not anticipated because although she had required daily medication her asthma was not severe at the time and she was ambulant. 5. Asthmatic patients of this type have a notoriously bad prognosis and often require very little to upset their delicately balanced respiratory state. Whether or not the use of Pyromen was causally related to her death it is impossible to say. It can be said with certainty that Pyromen had no demonstrable beneficial effect. 6. The pathological findings were limited to the respiratory tract. These showed a striking example of intense bronchial and bronchiolar obstruction due to mucus plugging and mucosal edema. The thymus was persistent. Death was due to asphyxia. REFERENCES
1. Walton,
C. H. A., Penner, D. W., and Wilt, J. C.: Sudden Death From Asthma, Can. Med. Assoc. J. 64: 95, 1951. Pyromen in the Treatment of Perennial Allergic 2. Randolph, T. G., and Rollins, J. P.: Symptoms, Ann. Allergy 8: 626, 1950.